The objectives of this K01 are twofold. 1) This K01 will support the Candidate to gain the additional training required for an independent interdisciplinary research career conducting complex biobehavioral, longitudinal research on the development of substance use and related phenotypes. 2) This K01 will clarify (aim 1) biobehavioral pathways of development and (aim 2) biological (genetic, endocrine) X environmental (prenatal, parenting) interactions that predict alcohol vs. tobacco vs. other drug use during adolescence. Understanding the development of substance use problems is a vital health concern because of the individual health and nationwide economic costs of dealing with substance use related injury, illness, death, crime, law enforcement, and lost productivity. Pathways and interactions by which genes, prenatal exposures, endocrine function, and parenting influence the development of substance use are not fully understood, in part because studies have not considered each of these influences together in the same developmental model. The research portion of this proposal tests two central hypotheses: 1) Prenatal exposures and subsequent endocrine development represent an important class of mechanisms by which genetic and parenting influences (specifically, parental negativity) are internalized, thus affecting behavioral development and subsequent substance use; and 2) Genetic influences can modify the influences of prenatal exposures and parental negativity, both of which can also modify the influence of endocrine development on adolescent substance use. Results from these aims will advance our knowledge of the origins of adolescent substance use, which adolescents will initiate and use which types of substances, and which developmental influences are most salient for substance use development given multiple other influences. Findings will also have implications for intervention by identifying optimal targets for enhancing protective mechanisms and disrupting mechanisms of risk for adolescent substance use given multiple other developmental influences. This K01 will also allow the Candidate the time and training required to build on her existing expertise and begin the transition to an independent, interdisciplinary researcher. Through training with experienced mentors who are leaders in the field, the Candidate will gain 1) expertise in novel statistical methods for analyzing genetic data 2) knowledge in mechanisms of prenatal risk, 3) knowledge of transitions from behavioral risk to adolescent substance use, 4) basic knowledge of the neural bases of adolescent hormone function and substance use, and 5) skills in integration and translation. Training in these areas and in research ethics is integral to completing the research aims, and preparing the Candidate for a career as a NIH-funded researcher investigating the adolescent substance use from a developmental perspective.